Antiphospholipid antibodies (APLA) are associated with arterial and venous thrombosis, as well as recurrent[unreadable] fetal loss, and are the most common cause of acquired thrombophilia. In vitro studies have suggested[unreadable] several mechanisms that might account for the pathogenic effects of these antibodies. APLA comprise a[unreadable] heterogeneous family of antibodies, and rather than binding anionic phospholipid as originally proposed,[unreadable] react preferentially with phospholipid binding proteins such as beta2 glycoprotein I (beta2GPI), prothrombin, or[unreadable] oxidized phospholipids; of these, beta2GPI is the most common. Several groups, including our own, have[unreadable] reported that APLA bind to endothelial cells, and we have recently demonstrated that "APLA"/anti-beta2GPI[unreadable] antibodies induce endothelial cell activation by cross-linking annexin II through binding of annexin ll-bound[unreadable] beta2GPI and initiation of an activation pathway involving TLR-4 and NF-KB. Despite these mechanistic[unreadable] observations, however, there are no specific markers of the prothrombotic state in patients with APLA. Two[unreadable] reports have suggested that increased levels of procoagulant microparticles circulate in the plasma of these[unreadable] patients; however, the origin of these microparticles, their association with "APLA" of defined specificity (i.e.[unreadable] anti-beta2GPI, anti-oxidized LDL), or their correlation with thrombotic events have not been well delineated. In[unreadable] Specific Aim 1 of this application, we propose to compare the levels of circulating microparticles in 200[unreadable] patients with APLA with those in 50 normal individuals. We will also determine the cellular origin of the[unreadable] circulating microparticles, and whether the number of microparticles or their cell of origin correlates with the[unreadable] serologic specificity of the "APLA". In Specific Aim 2, we will assess the correlation between the level of[unreadable] circulating microparticles and a clinical history of thrombosis, compare the procoagulant activity of[unreadable] microparticles from patients and controls, determine whether therapy of patients with "APLA" with aspirin[unreadable] and heparin reduces the level of microparticles, and evaluate the relationship between circulating[unreadable] microparticles and the ability of APLA to activate cells in vitro. In Specific Aim 3, we will assess the[unreadable] thrombogenicity of "APLA" in a mice, and determine the role of annexin II in thrombus formation. These[unreadable] clinical/translational studies should provide new information concerning the role of circulating microparticles[unreadable] in APLA-associated thrombosis, as well as the in vivo mechanisms of APLA in patients.